Relative Abuse Liability of GHB in Humans

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Lawrence P Carter1, Brian D Richards1, Miriam Z Mintzer1 and Roland R Griffiths*,1,2

1 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department

of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated

the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad

range of GHB doses (2–18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to

placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under

double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and

pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam

and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital

were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective

effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital.

Within participants, the dose–effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher

doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest

that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be

abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with

GHB appears to be greater.

Neuropsychopharmacology (2006) 31, 2537–2551. doi:10.1038/sj.npp.1301146; published online 26 July 2006

Keywords: GHB; triazolam; pentobarbital; drug abuse; subjective effects; human

INTRODUCTION use of GHB, which has been reported in North America (Miotto et al, 2001; Romanelli et al, 2003; Barrett et al, Gamma-hydroxybutyric acid (GHB) is a metabolite of the 2005), Europe (Bellis et al, 2003; Gonzalez and Nutt, 2005; inhibitory neurotransmitter gamma-aminobutyric acid Liechti et al, 2006), and Australia (Degenhardt et al, 2005). (GABA) that fulfills many of the criteria of a neurotrans- Despite these reports of recreational GHB use by humans, mitter (Maitre, 1997). GHB is used clinically for treatment the results of preclinical studies of the reinforcing effects of narcolepsy in the US (Xyrem; Fuller and Hornfeldt, of GHB in rodents and non-human primates have been 2003; Borgen et al, 2004) and for treatment of alcoholism in equivocal (for a review see Nicholson and Balster, 2001). Europe (Alcover; Poldrugo and Addolorato, 1999; Beghe` For example, GHB was not self-administered intravenously and Carpanini, 2000). Reports of GHB overdose (Caldicott (i.v.) in four monkeys trained to self-administer PCP et al, 2004; Kintz et al, 2005), withdrawal (Galloway (Beardsley et al, 1996), but was self-administered more et al, 1997), and drug-facilitated sexual assault (Schwartz than saline (but less than methohexital) by two out of three et al, 2000; Varela et al, 2004) have appeared in the monkeys trained to self-administer methohexital (Woolver- literature and are thought to be related to the recreational ton et al, 1999). In studies that have reported i.v. self- administration of GHB in mice, the total dose of GHB that *Correspondence: Dr RR Griffiths, Department of Psychiatry and was self-administered was either not reported (Martellotta Behavioral Sciences, Johns Hopkins UniversityFBPRU, 5510 Nathan et al, 1998) or was relatively low (5–7 mg/kg; Fattore et al, Shock Drive, Baltimore, MD 21224, USA, Tel: + 1 410 550-0034, Fax: + 1 410 550 0030, E-mail: [email protected] 2001) and there was no additional evidence to suggest that Received 14 February 2006; revised 24 May 2006; accepted 30 May the doses of GHB that were self-administered (0.05 and 2006 0.1 mg/kg/inf) were discriminable or had other behavioral Online publication: 31 May 2006 at http://www.acnp.org/citations/ effects. Rats have been shown to consume more of a GHB Npp053106060093/default.pdf (sodium salt) solution than water in a two-bottle choice Relative abuse liability of GHB in humans LP Carter et al 2538 procedure (Colombo et al, 1995); however, in the same drugs and without significant medical or psychiatric illness procedure, rats consumed the same amount of sodium (other than substance abuse). One participant reported chloride solution as GHB solution, and did so in a (salt) extensive past experience with GHB. Eleven participants concentration-dependent manner (Colombo et al, 1998). were Caucasian (79%) and three were African-American Lastly, GHB (175–350 mg/kg) has been shown to produce (21%). The median age of participants was 27 years conditioned place preference in rats; however, a greater (range: 20–43) and the median weight was 72 kg (range: number of conditioning trials was required with GHB than 60–98). Details regarding participant screening and with other classes of drugs such as opioids and ampheta- informed consent are similar to those described previously mines, suggesting that GHB might not be as reinforcing as (Griffiths et al, 1980). This study was approved by other drugs of abuse (Martellotta et al, 1997; Itzhak and Ali, the Institutional Review Board of Johns Hopkins Univer- 2002). Thus, results of the evaluation of the relative sity School of Medicine. Participants gave their written reinforcing effects of GHB in rodents and non-human informed consent before beginning the study and were paid primates have been somewhat inconsistent, which might be for their participation. partly due to the use of different species, routes of administration, doses, and behavioral end points. General Procedures Few clinical studies have evaluated abuse-related effects of GHB, and to our knowledge, no study has specifically After completing the screening procedures, eligible indivi- examined the abuse liability of supratherapeutic doses of duals were admitted to the residential behavioral pharma- GHB in a population of recreational sedative abusers. In one cology research unit at Johns Hopkins University Bayview study in opioid-dependent patients, 30 mg/kg (2.1 g/70 kg) Campus. Participants were informed that during their GHB was found to significantly increase subjective ratings participation they would receive various drugs, adminis- of ‘good mood,’ ‘spaced,’ ‘sluggish,’ and ‘carefree’ without tered orally, that could include sedatives, muscle significantly affecting psychomotor performance or ratings relaxants, antianxiety medications, antihistamines, stimu- of ‘liking’ (Rosen et al, 1997). In an unblinded outpatient lants, and weight loss medications. They were also informed study that evaluated the ability of a larger dose of GHB that one of the drugs they would receive would be (50 mg/kg or 3.5 g/70 kg tid) given three times daily for 24 GHB, an FDA-approved sleep-inducing agent for the weeks to promote abstinence from alcohol in alcohol- treatment of narcolepsy. The consent form also indicated dependent patients, approximately 10% of the patients that, ‘small doses [of GHB] usually produce an effect similar increased the dose of GHB by 6–7 times the therapeutic to alcohol’ and ‘larger doses induce loss of consciousness dose to 300–350 mg/kg tid (21–24.5 g/70 kg tid), suggesting and sleep.’ Other than receiving this general information, that GHB was reinforcing in this subset of alcoholic patients participants were blind to the type of drug administered (Addolorato et al, 1996). each day. Participants were told that the purpose of The present placebo-controlled, double-blind study was the study was to determine how different drugs affect undertaken to evaluate the relative abuse liability and to mood and behavior. Other than this general explanation of compare the psychomotor, subjective, and cognitive effects purpose, participants were given no instruction of what of GHB to triazolam and pentobarbital in participants with they were supposed to do or of what outcomes might be histories of sedative drug abuse. Triazolam and pento- expected, although they were required to practice the barbital were chosen as positive controls because these psychomotor and computer tasks (eg Circular Lights and compounds are known to be abused (Griffiths and Johnson, Computer Questionnaires) before the start of the study. 2005), have well-characterized positive reinforcing effects in Before admission to the residential unit, participants humans (Roache and Griffiths, 1985; Zawertailo et al, 2003), provided a urine sample that was screened for the presence are used for therapeutic indications similar to GHB (ie of commonly abused drugs. induction of sleep and alcohol withdrawal), and have On the first day of the study, participants received mechanisms of action similar to GHB (ie GABAergic). A 300 mg/70 kg pentobarbital under single-blind conditions to variety of psychomotor, subjective, and cognitive measures determine whether they reported liking the effects of this were assessed at different time points to characterize the dose of pentobarbital and for training and acclimation time course and peak effects of triazolam, pentobarbital, to the experimental procedures. This day also allowed and GHB at different doses. The experimental approach was for acclimation to the residential unit. Participants who similar to that used extensively to evaluate the relative abuse reported liking pentobarbital on the Next Day Question- liability of sedative/hypnotics (Griffiths et al, 2003), with the naire (described below) were allowed to continue in the exception that, due to the limited amount of information study. All participants reported liking 300 mg/70 kg available for selecting specific GHB doses and the antici- pentobarbital. Experimental sessions were conducted 5 pated steep dose–effect function for GHB, the design of this days per week (Monday to Friday), and participants study involved testing progressively increasing doses of followed a daily routine. GHB. Participants were awoken by 0700 hours and were allowed to smoke cigarettes until approximately 0800 hours. Participants were maintained on a caffeine-free diet for MATERIALS AND METHODS the duration of the study and were not allowed to eat or Participants drink caloric beverages from 0000 hours (ie midnight) the night before a session. Participants were allowed to smoke Participants were 12 adult male and two adult female cigarettes and eat after 1200 hours (ie noon) or after the subjects with histories of abuse of sedative/hypnotic drug effect dissipated, whichever occurred later. There did

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2539 not appear to be any signs of acute withdrawal (eg from Drugs nicotine or caffeine) over the course of this study. Lactose monohydrate (placebo; Amend Drug and Chemical The test room contained a hospital bed, two chairs, a Company, Irvington, NJ), triazolam (Upjohn Co., Kalama- desk, an Apple Macintosh computer (Apple Computer, Inc., zoo, MI), and pentobarbital (Abbott Labs, Abbott Park, IL) Cupertino, CA), and an automated ECG and blood pressure were orally administered in capsules. GHB (500 mg/ml monitor (Criticare Systems Inc., Waukesha, WI). A crash cart was available in case of a medical emergency. When not sodium oxybate solution) and GHB placebo (an equimolar sodium citrate (389 mg/ml) solution matched for pH) were actively completing an experimental task, participants were orally administered as solutions (Orphan Medical; Minne- allowed to engage in recreational activities (eg watching tonka, MN, now known as Jazz Pharmaceuticals, Palo Alto, television or reading). CA). The dose of GHB was adjusted by varying the During the study participants could receive a maximum volume of sodium oxybate in the administered solutions; of 13 different treatment conditions over 13 experimental however, the combined volume of sodium oxybate and sessions (placebo; 0.5 and 1.0 mg/70 kg triazolam; 200 and sodium citrate was always 40 ml to keep the sodium 400 mg/70 kg pentobarbital; and 2, 4, 8, 10, 12, 14, 16, and concentration constant. The total volume of the GHB 18 g/70 kg GHB). The order of the four drug and placebo and GHB placebo solutions that were administered was conditions (triazolam, pentobarbital, GHB, and placebo) was counterbalanced across participants. Within each type 400 ml and was prepared by diluting 40 ml of sodium oxybate and placebo or placebo alone with distilled/ of drug condition the sequence of the doses was always deionized water and fruit juice. ascending, and dosing within each type of condition was completed before proceeding to another type (eg both doses of triazolam were administered before proceeding Psychomotor Performance Measures to pentobarbital). The ascending sequence was used to determine the maximum dose of GHB that could be Balance. This task began with the participant raising one safely tolerated by individual participants and to avoid foot off of the floor with his or her eyes closed. The time adverse events that might result if an individual was that a participant remained on one foot without opening his particularly sensitive to GHB. For each participant, the or her eyes or touching the floor or another part of his or highest dose of GHB tested was one that produced her body with the raised foot was measured up to 30 s. severe functional impairment (ie the participant could Balance was measured for each foot and summed across not complete the subjective tasks and also had scores both feet. If a participant could not perform the task, a score of 0 on the psychomotor tasks at the same time point; of 0 s was recorded. for scoring procedures, see Psychomotor performance measures below). Circular Lights. The dependent measure for this previously When the highest dose of GHB had been determined, described button pressing task (Griffiths et al, 1983) was higher doses of GHB were removed from the dosing the number of correct presses (ie lights extinguished) in sequence and the remaining treatment conditions were 60 s. If a participant could not perform the task, a score administered in the previously determined order. For three of 0 was recorded. individuals, a dose of 6 g/70 kg GHB was inserted into the dose order between 4 and 8 g/70 kg because data from Digit-symbol-substitution task (DSST). This task was a earlier participants suggested that the GHB dose–effect computer version (McLeod et al, 1982) of the digit-symbol- curve was steep and that the effects of 8 g/70 kg GHB substitution task (Wechsler, 1958). The dependent measure were substantially stronger than those of 4 g/70 kg GHB. For was the number of correct patterns that was reproduced one of the three participants who received 6 g/70 kg GHB, within 90 s. If a participant could not perform the task, a this dose was also the highest dose tested (ie this person did score of 0 was recorded. not receive 8 g/70 kg GHB). On experimental days, lactose (placebo), triazolam, or Participant- and Observer-Rated Measures pentobarbital was administered in capsules and sodium citrate (GHB placebo) or GHB was administered as a Unless otherwise stated, all questionnaires were adminis- solution under double-blind, double-dummy conditions. tered on an Apple Macintosh computer. The participants Drug or placebo administration occurred at approximately and staff used a computer mouse to point and select 0845 hours and psychomotor performance tasks, subjective response options displayed on the computer monitor. measures, and the Digit Enter and Recall task were completed before administration (approximately 0800– Observer-rated measures. A previously described Obser- 0830 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after ver-Rated Questionnaire consisted of eight items rated on a administration. For safety monitoring, heart rate and blood five-point scale (Rush et al, 1999). Staff also rated pressure were assessed at these same time points and at participants’ level of alertness on a five-point scale 15 min intervals within the first 90 min after administration. consisting of the following five options: ‘5Fawake and On the last experimental day of the study (ie the ‘lottery alert,’ ‘4Fdrowsy, but easily aroused with verbal com- day’), participants received the consequence that was mands,’ ‘3Fdrowsy or asleep, responding to verbal and randomly selected from all of the choices that the light tactile stimulation,’ ‘2Fdrowsy or asleep, not participant made in the drug vs money Multiple Choice responding to loud voice, responding to rougher tactile Procedure (described below) and experimental procedures stimulation only,’ ‘1Fasleep, responding to pain only.’ In were conducted as usual. general, tactile stimulation consisted of touching or gently

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2540 shaking a drowsy or sleeping participant whereas nocicep- Macintosh computers (Roache and Griffiths, 1987). In the tive stimuli consisted of pressure applied to the nail bed of a first component of the task (enter), participants were finger or toe, or a sternal rub. instructed to reproduce the number using the keyboard while the number remained on the monitor. In the Drug Effect Questionnaire. This previously described second component of the task (recall), the participants questionnaire (Mumford et al, 1995), consisted of a five- were instructed to reproduce the number after 0 s (five point drug strength rating and a nine-point drug liking- trials) or 10 s (five trials) after the number disappeared disliking rating. For purposes of data analysis, ratings of from the monitor. The session ended after 10 eight-digit drug liking were assigned a score of 0 if participants numbers were correctly reproduced in the first component indicated disliking (Mumford et al, 1995). (ie 10 trials were initiated) or after the incorrect entry of 25 eight-digit numbers. The dependent measures were Subjective Effects Questionnaire. This previously described the percentage of eight-digit numbers that were correctly questionnaire (Rush et al, 1999) consisted of ratings of reproduced and the percentage of those numbers that sleepiness on a visual analog scale and ratings of 34 somatic were correctly recalled. and other subjective effects on a five-point scale. Word Recognition and Recall. For these tasks, 16 words Next Day Questionnaire. This previously described ques- were presented sequentially on a computer monitor 1 h after tionnaire (Rush et al, 1999), which was completed drug administration and participants were informed that approximately 24 h after drug administration, consisted of their memory for these words would be evaluated at a later five items rated on a five-point scale and two items time. Participants were required to rate the pleasantness answered with a numerical value in dollars and cents. of each word on a scale of 1 (least pleasant) to 7 (most pleasant) to encourage them to read and think about the words that were presented. At 5 h after the presentation of This proce- Drug vs money Multiple Choice Procedure. the words (6 h after drug administration), the Word Recall dure, which has been previously described in detail component commenced in which participants were asked (Griffiths et al, 1993; Mintzer and Griffiths, 1998) involves to recall as many words as they could remember from the an assessment of the participants’ preference to receive the words that were presented that morning. The dependent previously administered solution and capsules (a dose of measure was the number of correct words recalled (written drug or placebo) or an amount of money. Approximately, down) within 5 min. The Word Recognition task followed 24 h after drug administration, participants completed a the Word Recall task and consisted of the randomly series of 65 questions asking whether they would prefer to sequenced presentation of the 16 old words that had been receive, ‘yesterday’s drug’ or an amount of money. Positive presented earlier and 16 new words that were not previously and negative monetary values (À$40.00 to $40.00) were presented to the participant. Participants were instructed to included such that participants could gain (ie receive money respond by selecting a button on the monitor labeled, ‘old’ if instead of drug) or lose (ie pay to avoid the drug) money they recognized the word from the earlier presentation based on their preference for the drug. On the last session of of the words and to select on a button labeled, ‘new’ if they the study (ie the lottery day), one of the choices from this did not recognize the word from the prior presentation. procedure was randomly reinforced; the dose of drug or The dependent measure for the Word Recognition task placebo was administered and the amount of money was was d’, an index of the participant’s ability to discriminate credited to, or debited from, the participant’s account. The new and old words, which is calculated from the number of dose of drug or placebo was administered and the session old words identified as old and the number of new words was conducted as usual. The dependent measure was the identified as old (Snodgrass and Corwin, 1988). highest monetary value at which drug was chosen over money (ie the crossover point). Negative crossover points were analyzed as zeros to reduce the variability from Data Analyses participants that would pay varying amounts of money to For the Drug Effect Questionnaire, Subjective Effects avoid a drug. Questionnaire, and Observer-Rated Questionnaire, peak effect for each participant was defined as the maximum Pharmacological Class Questionnaire. This previously value from 0.5 to 12 h after drug administration. For the described questionnaire (Rush et al, 1999), which was Balance, Circular Lights, Digit Enter and Recall, DSST, completed approximately 24 h after drug administration, and observer ratings of level of alertness, peak effect for listed descriptive titles and examples of 12 classes of each participant was defined as the minimum value from psychoactive drugs, ‘blank or placebo,’ and ‘other.’ Parti- 0.5 to 12 h after drug administration. The General Linear cipants were instructed to choose the option that they Model (GLM) was used for all analysis of variance believed most closely represented the compound that they (ANOVA) calculations; all statistical tests were performed had received the previous day. Additionally, participants using SPSS (SPSS Inc., Chicago, IL) and po0.05 was completed a brief written description of the drug effects. considered significant. Two sets of analyses were conducted, dose–effect analyses Cognitive Performance Measures and time course analyses. Dose–effect analyses used one factor repeated measures ANOVA with condition (placebo, Digit Enter and Recall. This task was a version of the 0.5 and 1 mg/70 kg triazolam, 200 and 400 mg/70 kg number recall task that has been adapted for use on Apple pentobarbital, and three doses of GHB) as the factor (see

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2541 below). Planned comparisons (t-tests) between placebo and these results are reported only when the F statistic of the the seven active drug conditions, and between selected ANOVA was significant. doses of drugs, were conducted using the error variance for On the Pharmacological Class Questionnaire, correct the two means being compared; to minimize the chance of identification of triazolam and pentobarbital dose condi- Type I error, these results are reported only when the F tions as benzodiazepine or barbiturate varied among statistic of the ANOVA was significant. Data analyzed were participants, possibly reflecting different histories with peak psychomotor performance measures, peak ratings these compounds. Therefore, data from the Pharmacologi- from the Observer-Rated Questionnaire, Drug Effect Ques- cal Class Questionnaire are presented only for participants tionnaire, and Subjective Effects Questionnaire, ratings that (correctly) identified three out of the four doses of from the Next Day Questionnaire, crossover point from triazolam and pentobarbital as either a benzodiazepine or a the Multiple Choice Procedure, peak effects from the Digit barbiturate (N ¼ 6) and were not analyzed statistically. Enter and Recall task, and the number of words and d’ values from the Word Recall and Word Recognition tasks, respectively. RESULTS For the dose–effect analyses, because different partici- Ascending Dose Sequences and Level Of Sedation pants were exposed to different doses of GHB, statistical analyses were performed three different ways: (1) using 2, 4, In this ascending dose sequence design, all participants and 8 g/70 kg GHB in the 13 participants who received those received placebo and doses of 0.5 and 1.0 mg/70 kg doses (N ¼ 13); (2) using 2, 4, and 6 or 8 g/70 kg GHB triazolam, 200 and 400 mg/70 kg pentobarbital, and 2 (N ¼ 14) by combining the data for the one participant and 4 g/70 kg GHB. Each participant also received one or that received a maximum dose of 6 g/70 kg with those more higher doses of GHB, up to a dose that produced that received 8 g/70 kg; and (3) using 2, 4 g/70 kg, and severe functional impairment (ie the participant could not the highest dose of GHB that each participant received complete the subjective tasks and also had scores of 0 on the (N ¼ 14), which was 6 g/70 kg for one participant, 8 g/70 kg psychomotor tasks at the same time point). The highest for nine participants, 10 g/70 kg for two participants, 12 g/ dose of GHB that was received varied markedly across the 70 kg for one participant, and 18 g/70 kg for one participant. participants (6 g/70 kg, N ¼ 1; 8 g/70 kg, N ¼ 9; 10 g/70 kg, In general, the qualitative and quantitative results of N ¼ 2; 12 g/70 kg, N ¼ 1; and 18 g/70 kg, N ¼ 1). analysis 1 using only participants that received 8 g/70 kg On the observer-rated level of alertness scale, all GHB (N ¼ 13) was very similar to analysis 2 that combined three drugs produced dose-related increases in sedation the data for the one participant that received a maximum as reflected in the peak minimum level of alertness dose of 6 g/70 kg with those that received 8 g/70 kg; there- ratings (Table 1). Both doses of triazolam and pentobarbital fore, only data from analyses 1 and 3 are presented and produced ratings of drowsy or asleep on the level of discussed here. alertness scale. In contrast, the majority of participants Time course analyses examined the effects of measures remained awake and alert after administration of 2 or assessed repeatedly after drug administration. These 4 g/70 kg GHB. The larger dose of 8 g/70 kg GHB, like 1 mg/ analyses used two-factor repeated measures ANOVA with 70 kg triazolam and 400 mg/70 kg pentobarbital, produced condition (placebo, 0.5 and 1 mg/70 kg triazolam, 200 and some level of sedation in almost all (490%) participants; 400 mg/kg pentobarbital, and 2, 4, and 8 g/70 kg GHB) and however, unlike 1 mg/70 kg triazolam and 400 mg/70 kg time (0.5, 1, 2, 3, 4, 6, 8, and 12 h after drug) as factors pentobarbital, 8 g/70 kg GHB produced a greater level of (N ¼ 13). Planned comparisons (t-tests) of placebo with sedation in some participants (Table 1). In almost one-third each of the drug conditions at each postdrug time point of the participants that received 8 g/70 kg GHB (31%), were conducted using the error variance for the two means nociceptive (ie painful) stimuli were required to elicit a being compared; to minimize the chance of Type I error, response from the participant, whereas nociceptive stimuli

Table 1 Peak Minimum Observer-Rated Level of Alertnessa

Triazolam (mg/70 kg) Pentobarbital (mg/70 kg) GHB (g/70 kg)

Level of alertness ratingb Placebo 0.5 1 200 400 2 4 8 Highestc

Awake and alert 93 29 7 21 0 86 64 8 0 Drowsy, but easily aroused with verbal commands 7 43 29 64 36 14 36 15 0 Drowsy or asleep, responding to verbal and light 029431450003129 tactile stimulation Drowsy or asleep, not responding to loud voice, 0 0 21 0 14 0 0 15 36 responding to rougher tactile stimulation only Asleep, responding to pain only 0 0 0 0 0 0 0 31 36 aData show the percentage of participants that were assessed as reaching the indicated level of alertness rating in each dose condition (N ¼ 14 for each condition except 8 g/70 kg GHB, N ¼ 13). bPeak minimum rating of level of alertness for the 3 h period after drug administration. cHighest dose of GHB that each individual participant received.

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2542 were never required after administration of 1 mg/70 kg triazolam and GHB typically did not last more than 3–4 h triazolam or 400 mg/70 kg pentobarbital. After the highest whereas a dose of pentobarbital (ie 400 mg/70 kg) that dose of GHB that was administered, all participants produced effects similar to those of 1 mg/70 kg triazolam exhibited substantial sedation and more than two-thirds and 8 g/70 kg GHB had significant behavioral and subjective (10 out of 14 or 71%) required rough tactile, or nociceptive, effects up to 6–8 h after administration (eg Figure 1, stimuli for arousal. Despite the marked sedation that was DSST and Observer-rated drug strength). The highest observed after large doses of GHB, respiration and blood doses of triazolam and pentobarbital significantly increased pressure were well maintained and recovery from a strong heart rate (by 12.572.5, and 9.973.3 beats per min GHB drug effect was generally rapid with participants often (b.p.m.), respectively, 1 h after administration), which was reporting feeling alert and well rested upon awakening. maximal at 1 h (data not shown). The dose of 8 g/70 kg GHB significantly decreased heart rate (by 14.972.9 b.p.m. at Time Course of Drug Effects 2 h), which was maximal at 2 h. There were no marked effects on systolic or diastolic blood pressure following any Triazolam, pentobarbital, and GHB exhibited dose- and of the drugs (data not shown). time-related behavioral, observer-rated, and participant- rated effects. Figure 1 shows the time course of triazolam, Psychomotor Performance and Observer-Rated pentobarbital, and GHB on three measures (Circular Lights, Measures DSST, and Observer-ratings of drug strength) that are representative of the general time course of these drugs Triazolam, pentobarbital, and GHB significantly decreased across each of the procedures used in this study. Each drug participants’ psychomotor performance and observer-rated significantly decreased performance on the Circular Lights level of alertness and increased observer-rated muscle and DSST tasks and increased Observer-rated measures of relaxation, abnormal posture, and drug strength relative drug strength (Figure 1). In general, maximal drug effects to placebo (Table 2). In general, the peak effects of 1 mg/ occurred 1–2 h after administration of each drug, although 70 kg triazolam, 400 mg/70 kg pentobarbital, and 8 g/70 kg significant drug effects were observed as early as 30 min GHB on psychomotor performance and observer-rated after administration of pentobarbital and larger doses of measures were not markedly different from each other GHB (eg Figure 1, observer-rated drug strength). The (Table 2; Figure 2). The highest dose of GHB that was duration of action of pentobarbital tended to be longer than administered to each participant was, by design, a dose that of triazolam and GHB; for example, the effects of that produced behavioral impairment. The rightmost

Figure 1 Time course of effects of triazolam (left panels), pentobarbital (center panels), and GHB (right panels) on circular lights, DSST, and observer- rated drug strength. Y axes: correct responses (Circular Lights and DSST) and ratings (observer-rated drug strength). X axes: time after drug administration in hours (0 indicates predrug). Data points show means (N ¼ 13); brackets show + or À1 SEM. Filled symbols indicate values that are significantly different from the corresponding placebo value at the same time point (po0.05, planned comparisons).

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2543 column in Table 2 indicates that the highest dose of GHB Participant-Rated Measures administered to each participant resulted in significantly lower psychomotor performance and level of alertness, and Same-day participant-rated measures. As shown in the top greater observer ratings of drug strength compared to the panel of Figure 3, triazolam, pentobarbital, and GHB highest dose of pentobarbital (400 mg/70 kg) that was produced dose-related increases in participants’ same-day administered. ratings of drug effect. Similar dose-related increases were

Table 2 Summary of Significant Drug Effects and Comparisons between Selected Doses on Measures that could be Assessed at all Scheduled Time Points (ie, Assessment was not Precluded by Nonresponding at High GHB Doses)

Comparisons of drug vs placeboa Comparisons of drug vs drugb

1 TRZ vs 1 TRZ vs 400 PTB vs 400 PTB vs Highest Measures TRZ vs PL PTB vs PL GHB vs PL 8 GHB 400 PTB 8 GHB GHB dosec

Psychomotor performance (peak effects)d DSST ÀÀ ÀNS NS NS GHB4PTB Circular Lights ÀÀ ÀNS NS NS GHB4PTB Balance ÀÀ ÀNS PTB4TRZ NS NS

Observer-rated measures (peak effects)e Muscle relaxation + + + NS NS NS GHB4PTB (locomotor) Abnormal posture + + + NS NS NS GHB4PTB Drug strength + + + NS NS NS GHB4PTB Level of alertness ÀÀ ÀGHB4TRZ NS GHB4PTB GHB4PTB

Next day participant-rated measures Drug strength Strength + + + NS NS NS GHB4PTB ‘Positive’ drug effects Liking + + + NS PTB4TRZ NS NS Good effects + + + NS PTB4TRZ NS NS

‘Negative’ drug effects Bad effects + NS + NS NS GHB4PTB GHB4PTB

Indirect measures of drug reinforcement Take again + + + NS PTB4TRZ NS NS Worth on the street + + + GHB4TRZ PTB4TRZ NS NS Willing to pay + + + GHB4TRZ PTB4TRZ NS NS

Direct measure of drug reinforcement Crossover point (MCP) + + + GHB4TRZ PTB4TRZ NS NS aThese three columns show the results of planned comparisons of the effects of placebo with 0.5 and 1 mg/70 kg triazolam (TRZ), 200 and 400 mg/70 kg pentobarbital (PTB), and 2, 4, and 8 g/70 kg GHB (N ¼ 13). Symbol (+ or À) indicates that at least one dose of the drug was significantly different from placebo (po0.05); symbol (+ or À) also indicates the direction of the drug effect relative to placebo. NS indicates that no dose of that drug was different from placebo. bThese four columns show the results of planned comparisons for selected doses of different drugs. The first three columns show comparisons between the highest dose of triazolam (1 mg/70 kg), the highest dose of pentobarbital (400 mg/70 kg), and 8 g/70 kg GHB (N ¼ 13). The rightmost column shows the comparison between the highest dose of pentobarbital (400 mg/70 kg) and the highest dose of GHB that each individual participant received (6–18 g/70 kg GHB; N ¼ 14). The drug to the left of the symbol (4) produced a significantly greater effect. NS indicates that the effects produced by the doses of the two drugs were not significantly different. cBecause the high dose of pentobarbital (400 mg/70 kg) generally produced greater effects than the high dose of triazolam (1 mg/70 kg), the comparison of the high dose of GHB with the high dose of pentobarbital was of greatest interest. Thus, for simplicity, the high dose triazolam vs the high dose GHB comparison is not presented. dAs described in the Materials and methods, if a participant could not perform a psychomotor task at a time point because of a strong drug effect, a score of 0 was recorded for that time point. eFive observer-rated measures are not shown because an appropriate rating could not be assigned in the absence of behavior (ie, when a participant was not awake at high GHB doses) (sedation/sleepiness, nonlocomotor muscle relaxation, speech, confusion/disorientation, and stimulation/arousal).

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2544

Figure 2 Psychomotor performance and observer-rated effects of triazolam, pentobarbital, and GHB. Y axes: score or rating expressed as peak effect; peak effects for psychomotor performance measures are the minimum values and peak effects for the observer-rated measures are the maximum values across the 12 h session. X axes: dose in mg (triazolam and pentobarbital) or g (GHB) per 70 kg (log scale); PL designates placebo. Data points show means (N ¼ 13); brackets show 71 SEM and the absence of brackets indicates that 1 SEM fell within the area of the data symbol. Filled symbols indicate values that are significantly different from placebo; letters above 1 mg/70 kg triazolam, 400 mg/70 kg pentobarbital, and 8 g/70 kg GHB indicate that these values are significantly different from the dose of drug designated by the letter (t, p, and g for 1 mg/70 kg triazolam, 400 mg/70 kg pentobarbital, and 8 g/70 kg GHB, respectively; po0.05; planned comparisons).

shown on most same-day participant ratings of somatic With regard to likelihood of abuse, triazolam, pentobar- and positive subjective effects. Table 3 summarizes the bital, and GHB significantly increased same-day measures differences in peak subjective effects for all of the same-day of positive drug effects (eg liking and good effects) relative participant-rated measures. It should be noted that these to placebo. In general, the magnitude of peak same-day measures could not be assessed at all time points because participant ratings of positive drug effects did not differ of nonresponding (ie marked sedation), which occurred between triazolam, pentobarbital, and GHB, although, most often after 8 g/70 kg GHB and the highest dose of GHB 400 mg/70 kg pentobarbital was rated as having significantly that participants received. For subjective effects that greater good effects than 1 mg/70 kg triazolam and 8 g/70 kg were significantly increased relative to placebo, tria- GHB (Table 3). Further, each of the measures of liking, zolam, pentobarbital, and GHB exhibited similar profiles like, and good effects were rated significantly greater after across subjective effects, although GHB, unlike triazolam 400 mg/70 kg pentobarbital than after the highest dose of and pentobarbital, did not significantly increase ratings of GHB that each participant received (Table 3, right column). slurred speech, forgetful, comfortable, or relaxed, at any These apparent differences shown in Table 3 in liking dose (Table 3). Comparing the magnitude of subjective between the 8 g/70 kg dose of GHB relative to pentobarbital effects across drugs, in general, participants’ same-day vs the highest dose of GHB that each participant received ratings of subjective effects after 400 mg/70 kg pentobar- relative to pentobarbital might have been a result of greater bital were significantly greater than those after 1 mg/70 kg ‘negative’ drug effects associated with higher doses of triazolam or the highest dose of GHB (Table 3), despite GHB (Figure 3, bottom panels; Table 3). GHB was the similar or greater effects of the highest dose of GHB only compound that significantly increased same-day compared to 400 mg/70 kg pentobarbital on psychomotor participant ratings of queasy or sick to stomach and performance and observer ratings of sedation and drug headache (Figure 3). Same-day ratings of queasy or sick strength (cf., Table 2). to stomach were significantly greater after 8 g/70 kg GHB

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2545 these direct and indirect measures of reinforcement, the effects of 400 mg/70 kg pentobarbital were significantly greater than 1 mg/70 kg triazolam, but not significantly different from those of 8 g/70 kg GHB or the highest dose of GHB that each participant received (Figure 4; Table 2, right column). The absence of differences in drug reinforcement between GHB and pentobarbital is notable given that the highest dose of GHB that was received produced significantly greater ratings of drug strength than the highest dose of pentobarbital (Table 2, right column). Figure 4 (top right panel) also shows that all three doses of GHB and the highest dose of triazolam significantly increased next-day ratings of bad effects. Consistent with significant increases in same-day participant ratings of queasy or sick after GHB (Figure 3), open-ended comments on the Next Day Questionnaire indicated that nausea, gastrointestinal (GI) distress, diarrhea, or vomiting were common after doses of GHB (ie occurred after 41 and 78% of sessions in which 2–8 and 10–18 g/70 kg GHB were administered, respectively, compared with 4% and 14% of sessions in which triazolam and pentobarbital were administered, respectively). These negative effects were cited by participants as contributing to their disliking of GHB. In contrast, open-ended comments after triazolam uniformly cited memory loss as contributing to their disliking of the drug.

Pharmacological Class Questionnaire. Of the fourteen participants, six reliably identified doses of triazolam and pentobarbital as either a benzodiazepine or barbiturate on the next-day Pharmacological Class Questionnaire. In this subset of participants, five out of six (83%) identified Figure 3 Ratings of same-day drug effect, queasy or sick to stomach, and placebo as a blank or placebo, six out of six (100%) headache for triazolam, pentobarbital, and GHB. Y axes: peak same-day identified 0.5 and 1 mg/70 kg triazolam as a benzodiazepine ratings (Subjective Effects Questionnaire); peak effects are the maximum values across the 12 h session. X axes: dose in mg (triazolam and or barbiturate, and four out of six (67%) identified 200 and pentobarbital) or g (GHB) per 70 kg (log scale); PL designates placebo. 400 mg/70 kg pentobarbital as a benzodiazepine or barbitu- Data points show means (N ¼ 13); brackets show 71 SEM. See Figure 2 rate (data not shown). The dose of 2 g/70 kg GHB was most for other details. commonly identified as a benzodiazepine or barbiturate with two out of six participants (33%) selecting this class, whereas after 4 g/70 kg GHB two out of six participants and after the highest dose of GHB that each participant each chose blank or placebo, opiate, or other. The ‘other’ received compared to 400 mg/70 kg pentobarbital (Figure 3; category was most commonly chosen after 8g/70 kg GHB Table 3). (three out of six, 50%), followed by opiate (two out of six, 33%), and benzodiazepine or barbiturate (one out Next-day participant-rated measures. On next-day ratings of six, 17%; data not shown). of drug strength, all three drugs produced similar dose- related increases (Figure 4, top left panel; Table 2). All three Cognitive Performance Measures drugs significantly increased next-day participant ratings of positive subjective effects (liking and good effects), indirect In general, the impairment of memory processes by GHB measures of drug reinforcement (take again, worth on the appeared to be less than what was observed following street, and willing to pay), and a direct measure of drug triazolam or pentobarbital (Figure 5). On a Digit Enter and reinforcement (crossover point from the Multiple Choice Recall task, triazolam, pentobarbital, and GHB significantly Procedure; Figure 4; Table 2). In general, the next-day decreased the peak percentage of eight-digit numbers indirect and direct measures of drug reinforcement after that were correctly entered; however, only triazolam 400 mg/70 kg pentobarbital and 8 g/70 kg GHB were greater and pentobarbital significantly decreased the percentage than those after 1 mg/70 kg triazolam (Figure 4; Table 2). of numbers that were recalled after each delay condition Specifically, next-day participant-rated measures after (Figure 5, top three panels). The peak effects of 8 g/70 kg administration of 8 g/70 kg GHB were significantly greater GHB were significantly less than 1 mg/70 kg triazolam and than those after 1 mg/70 kg triazolam for worth, willing to 400 mg/70 kg pentobarbital on the recall component, but pay, and the crossover point from the Multiple Choice not the enter component, suggesting that up to doses Procedure (Figure 4, right panels), but not for take again, that produced comparable deficits in performance on the liking, and good effects (Figure 4, left panels). For all of enter component, GHB did not significantly affect the

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2546 Table 3 Summary of Significant Drug Effects and Comparisons between Selected Doses on Measures that could not be Assessed at all Scheduled Time Points Due to Nonresponding at High Drug Dosesa,b

Comparisons of drug vs placeboc Comparisons of drug vs drugd

1 TRZ vs 1 TRZ vs 400 PTB vs 400 PTB vs Highest Measures TRZ vs PL PTB vs PL GHB vs PL 8 GHB 400 PTB 8 GHB GHB dosee

Same day participant-rated measures (peak effects) Drug strength Strength (DEQ)f + + + GHB4TRZ PTB4TRZ NS GHB4PTB Drug effect (SEQ)g + + + NS PTB4TRZ NS NS

Somatic and other subjective effects (SEQ) Alert/sleepy VAS + + + NS PTB4TRZ PTB4GHB PTB4GHB Depressant or sedating + + + NS PTB4TRZ PTB4GHB PTB4GHB Confused or disoriented + + + NS PTB4TRZ PTB4GHB PTB4GHB Sleepy + + + NS PTB4TRZ PTB4GHB PTB4GHB Blurred vision + + + NS PTB4TRZ PTB4GHB PTB4GHB Dry mouth + + + NS NS NS GHB4PTB Limp or loose + + + NS NS NS NS Light-headed or dizzy + + + GHB4TRZ PTB4TRZ NS NS Fatigued or weak + + + NS NS PTB4GHB NS Unsteady + + + GHB4TRZ PTB4TRZ PTB4GHB PTB4GHB Difficulty concentrating + + + NS PTB4TRZ PTB4GHB PTB4GHB Slurred speech + + NS NS NS PTB4GHB PTB4GHB Mentally slowed + + + NS PTB4TRZ PTB4GHB PTB4GHB Tired or lazy + + + NS PTB4TRZ PTB4GHB PTB4GHB Easy going or mellow + + + NS NS PTB4GHB PTB4GHB Forgetful + + NS NS NS PTB4GHB PTB4GHB Comfortable NS + NS NS PTB4TRZ PTB4GHB PTB4GHB Relaxed + + NS NS NS PTB4GHB PTB4GHB

‘Positive’ drug effects Liking (DEQ) + + + NS NS NS PTB4GHB Like (SEQ) + + + NS NS NS PTB4GHB Good effects (SEQ) + + + NS PTB4TRZ PTB4GHB PTB4GHB

‘Negative’ drug effects Headache (SEQ) NS NS + GHB4TRZ NS NS NS Queasy or sick to stomach (SEQ) NS NS + GHB4TRZ NS GHB4PTB GHB4PTB

aMissing data due to periods of nonresponding at high doses: (1) a total of 5 time points in four participants after 1 mg/70 kg triazolam; (2) a total of 5 time points in two participants after 400 mg/70 kg pentobarbital; (3) a total of 21 time points in eight participants after 8 g/70 kg GHB; and (4) a total of 29 time points in eleven participants after the highest dose of GHB that each participant received. bEleven participant-rated measures are not shown because the F statistic was not significant (arousing or stimulant, hot or flushed, limbs heavy or rigid, talkative, excited, nervous or anxious, numbness or tingling, restless, energetic, shaky or jittery, and irritable or grumpy). cThese three columns show the results of planned comparisons of placebo with 0.5 and 1 mg/70 kg triazolam (TRZ), 200 and 400 mg/70 kg pentobarbital (PTB), and 2, 4, and 8 g/70 kg GHB (N ¼ 13). Symbol (+ or À) indicates that at least one dose of the drug was significantly different from placebo (po0.05); symbol (+ or À) also indicates the direction of the drug effect relative to placebo. NS indicates that no dose of that drug was different from placebo. dThese four columns show the results of planned comparisons for selected doses of different drugs. The first three columns show comparisons between the highest dose of triazolam (1 mg/70 kg), the highest dose of pentobarbital (400 mg/70 kg), and 8 g/70 kg GHB (N ¼ 13). The rightmost column shows the comparison between the highest dose of pentobarbital (400 mg/70 kg) and the highest dose of GHB that each individual participant received (6–18 g/70 kg GHB; N ¼ 14). The drug to the left of the symbol (4) produced a significantly greater effect. NS indicates that the effects produced by the doses of the two drugs were not significantly different. eBecause the high dose of pentobarbital (400 mg/70 kg) generally produced greater effects than the high dose of triazolam (1 mg/70 kg), the comparison of the high dose of GHB with the high dose of pentobarbital was of greatest interest. Thus, for simplicity, the high dose triazolam vs the high dose GHB comparison is not presented. fDEQ ¼ Drug Effect Questionnaire. gSEQ ¼ Subjective Effects Questionnaire.

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2547

Figure 4 Next-day ratings of drug strength, bad effects, good effects, liking, and indirect and direct measures of reinforcement for triazolam, pentobarbital, and GHB. Y axes: next-day ratings (Next Day Questionnaire) and crossover point (Multiple Choice Procedure). X axes: dose in mg (triazolam and pentobarbital) or g (GHB) per 70 kg (log scale); PL designates placebo. Data points show means (N ¼ 13); brackets show 71 SEM. See Figure 2 for other details. participants’ performance on the 0 or 10 s delayed recall which words they had seen before), whereas GHB did not component. (Figure 5, bottom panel showing significantly lower d’ In a Word Recall task designed to test the participants’ values after administration of triazolam and pentobarbital ability to remember words that they had seen 5 h earlier, compared to placebo or 4 g/70 kg GHB). Unlike the Word doses of triazolam and pentobarbital decreased the mean Recall task, data from the Word Recognition task show that (71 SEM) number of words that were recalled from the highest dose of GHB that could be studied in these 3.270.7 after placebo to less than one word after any dose participants (ie they were awake to study the words 1 h after of triazolam or pentobarbital (Figure 5, fourth panel). The GHB administration) did not affect the participants’ ability effects of 8 g/70 kg GHB on the Word Recall (and Word to discriminate new and old words. Recognition) tasks were not analyzed because fewer than half of the participants were able to complete the word study part of the task 1 h after administration of 8 g/70 kg DISCUSSION GHB; however, 4 g/70 kg GHB had less of an effect on Word Recall than 0.5 mg/70 kg triazolam or 200 mg/70 kg pento- One aim of this study was to assess the relative likelihood of barbital (Figure 5, fourth panel). abuse of GHB compared to triazolam and pentobarbital in In the Word Recognition task, triazolam and pento- human participants that use sedatives recreationally. In barbital significantly decreased the participants’ ability to these participants, all next-day measures of reinforcing discriminate between new and old words (ie remember effects and positive drug effects of pentobarbital were

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2548 greater than those of triazolam, which is consistent with increased same-day and next-day measures of positive previous human and non-human laboratory studies that subjective effects and measures of drug reinforcement have compared the reinforcing effects of these compounds relative to placebo. Although GHB was tested at doses that (Griffiths et al, 1981, 1985; Roache and Griffiths, 1985). GHB produced substantially greater sedation than triazolam and pentobarbital (cf., Tables 1 and 2), the measures of positive subjective effects and of drug reinforcement after GHB were never statistically greater than pentobarbitalFin fact, they were generally numerically smaller (five of six measures in Figure 4.), and sometimes statistically smaller than the high dose of pentobarbital (Table 3). In contrast, these effects of GHB were always numerically greater than the high dose of triazolam (six of six measures in Figure 4), and sometimes statistically greater (Table 2). In addition, GHB generally produced greater unpleasant drug effects (ie headache, sick to stomach, bad effects) than both triazolam or pentobarbital (cf., Figures 3 and 4; Tables 2 and 3). Overall, the relative likelihood of abuse of GHB is intermediate to that of triazolam and pentobarbital. The time course of drug effects can influence the reinforcing effects and likelihood of abuse of drugs (Griffiths et al, 1985; Mumford et al, 1995). In the current study, high doses of pentobarbital and GHB tended to exhibit a faster onset of action (30 min) than triazolam (1 h), and the duration of action of pentobarbital was longer (6–8 h) than triazolam or GHB (2–4 h; cf., Figure 1). It is possible that the faster onset of action of pentobarbital and GHB compared to triazolam, or the longer duration of action of pentobarbital relative to triazolam and GHB (cf., Mintzer and Griffiths, 2005), might have contributed to greater participant ratings of direct and indirect measures of reinforcement (ie crossover point, worth, and willing to pay were significantly greater after pentobarbital and GHB than triazolam). Consistent with the shared therapeutic indications of triazolam, pentobarbital, and GHB (induction of sleep and treatment of alcohol withdrawal), all three drugs decreased psychomotor performance and observer-rated level of alertness, increased observer ratings of muscle relaxation and abnormal posture, and increased participant ratings of sleepy, depressant or sedating, tired or lazy, and easy going or mellow. Triazolam, pentobarbital, and GHB did not increase participant ratings of arousing or stimulant, excited, restless, energetic, or shaky or jittery at any dose studied. Such a profile of effects for these drugs is consistent with previous findings with triazolam and pentobarbital (Mintzer et al, 1997; Rush et al, 1999) and extends previous findings with GHB (eg Rosen et al, 1997; Ferrara et al, 1999)

Figure 5 Cognitive performance measures for triazolam, pentobarbital, and GHB. Y axes: percentage of numbers entered or recalled (digit enter and recall), number of words recalled (Word Recall), and discriminative index (d0; Word Recognition). Data from the Digit Enter and Recall task are expressed as peak effects (minimum values across the 12 h session); the Word Recognition and Recall task was performed once per session. X axes: dose in mg (triazolam and pentobarbital) or g (GHB) per 70 kg (log scale); PL designates placebo. Data points show means (N ¼ 13); brackets show 71 SEM. Data for 8 g/70 kg GHB are not shown for the Word Recognition and Word Recall tasks because less than half of the participants completed the word study task 1 h after administration. Letters above 4 g/70 kg GHB for the Word Recall and Word Recognition tasks indicate that these values are significantly different from 1 mg/70 kg triazolam and 400 mg/70 kg pentobarbital; po0.05; planned comparisons. See Figure 2 for other details.

Neuropsychopharmacology Relative abuse liability of GHB in humans LP Carter et al 2549 by characterizing large, supratherapeutic doses of GHB effects of 400 mg/70 kg pentobarbital was also generally across a broad range of measures. greater than that of 1 mg/70 kg triazolam at doses that Although there were substantial similarities in subjective produced equivalent deficits in psychomotor performance effects of the three drugs, GHB produced greater unpleasant and observer-rated measures of sedation is consistent with a effects than either pentobarbital or triazolam. Consistent previous finding that participants tend to underestimate the with reports of GHB use outside of the laboratory setting (eg effects of triazolam relative to pentobarbital (Roache and Miotto et al, 2001; Degenhardt et al, 2002), GHB signifi- Griffiths, 1985). cantly increased same-day participant-ratings of headache Given that many clinical reports describing GHB abuse and queasy or sick to stomach and next-day ratings of bad and ‘date-rape’ claim that GHB produces robust antero- effects. Nausea, GI distress, diarrhea, or vomiting occurred grade amnesia (eg Schwartz et al, 2000; Varela et al, 2004), it during 41 and 78% of the sessions in which doses of 2–8 is interesting that the effects of GHB on memory processes and 10–18 g/70 kg GHB were administered, respectively, in this study were significantly less than those of triazolam which is consistent with the high frequency of adverse and pentobarbital. Specifically, the findings presented in GI effects of GHB described in other clinical reports of Figure 5 indicate that GHB, unlike triazolam and pento- GHB toxicity (eg Degenhardt et al, 2002; Couper et al, 2004; barbital, did not impair participants’ recall of eight-digit Liechti et al, 2006). Unlike GHB, reports of nausea, GI numbers when they were able to replicate (enter) those distress, diarrhea, or vomiting after doses of triazolam or numbers. Further, at doses in which participants were pentobarbital occurred after only 4 and 14% of sessions, able to study a list of words, GHB did not impair the respectively. In open-ended written comments on the Next participants’ ability to discriminate new and old words 5 h Day Questionnaire, participants that reported disliking later. Taken together, these data show that up to doses GHB cited effects such as nausea, GI distress, and loss of that prevented the assessment of cognitive effects (eg loss consciousness as reasons for disliking the drug. Thus, it of consciousness) the effects of GHB on these memory is possible that the unpleasant effects of GHB might limit tasks were significantly less than those of triazolam and the liability of GHB for abuse by people who are sensitive to pentobarbital and not significantly different from placebo. these adverse effects. The finding that the impairment of participants’ free recall Despite an overlapping profile of subjective effects among of words after 4 g/70 kg GHB was significantly greater than triazolam, pentobarbital, and GHB, GHB was rarely after placebo, but significantly less than after triazolam or identified as a benzodiazepine or barbiturate and identifica- pentobarbital, is consistent with previous reports that have tion of GHB as either a barbiturate or a benzodiazepine shown that the impairment of memory processes by GHB, was not dose-related. This finding is consistent with GHB when observed (eg Grove-White and Kelman, 1971) was less occasioning little or no drug-appropriate responding in than the impairment produced by benzodiazepines and rhesus monkeys trained to discriminate triazolam or barbiturates (diazepam, methohexitone, and quinalbarbi- pentobarbital (Woolverton et al, 1999), and with triazolam tone; Metcalf et al, 1966; Grove-White and Kelman, 1971). and pentobarbital (positive GABAA receptor modulators) Thus, it is possible that the ‘amnesia’ that is often attributed having different pharmacological mechanisms of action to GHB in clinical reports is due to loss of consciousness than GHB, which is a GABAB receptor agonist (Mathivet and not any selective impairment of memory processes. et al, 1997) and specific GHB receptor ligand (Benavides Further characterization of the effects of GHB across et al, 1982). Given that the prototypical GABAB receptor procedures that are designed to test different aspects of agonist baclofen (Lioresal) is used therapeutically as a memory might help determine whether GHB affects specific muscle relaxant, it is somewhat surprising that GHB was not memory processes. identified as a muscle relaxant more often (two participants GHB intoxication and overdose have been well docu- identified a dose of GHB as a muscle relaxant; one after 2 g/ mented in case reports (Freese et al, 2002; Bosman and 70 kg and one after 4 g/70 kg GHB), although this result Lusthof, 2003; Degenhardt et al, 2003; Liechti et al, 2006). might be due to participants’ lack of experience with this One explanation for the apparently high frequency of class of compounds (muscle relaxants). accidental GHB overdose (ie a greater level of sedation Given that the design of this study included evaluating than intended, sometimes resulting in medical inter- doses of GHB up to those that produced behavioral vention), even among experienced users (Miotto et al, impairment and greater observer-rated sedation than 2001; Degenhardt et al, 2002, 2003), is the variability of triazolam and pentobarbital, it might be expected that the volume, concentration, and identity of GHB solutions on peak subjective effects of GHB would be greater than those the street (eg GHB precursors or analogs are sold as of triazolam or pentobarbital. However, the same-day peak substitutes for GHB; Zvosec et al, 2001), which makes it subjective effects of 400 mg/70 kg pentobarbital were difficult to estimate a desired dose for self-administration generally greater than those of the 8 g/70 kg GHB dose and (Degenhardt et al, 2003). In this study, known doses of the highest dose of GHB that was received (cf., Table 3, two GHB were administered on a weight-adjusted basis and rightmost columns), indicating that when participants were under controlled conditions, thereby eliminating the able to respond, they rated the effects of GHB lower than the aforementioned sources of variability and the possibility highest dose of pentobarbital. A major factor contributing of cointoxicants. The data show that even under these to this dissociation between observer-rated sedation and conditions, substantial differences in sensitivity to GHB can peak magnitude of subjective effect is that there were more exist, at least in recreational sedative users. That GHB occasions of nonresponding at time of peak effects after produced qualitatively similar subjective effects as classic high doses of GHB than after triazolam or pentobarbital sedatives, but to a lesser magnitude, might account for some (Table 3). The finding that the magnitude of peak subjective cases of unintended GHB overdose in experienced sedative

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